NDLI: Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response

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Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response

Content Provider	Semantic Scholar
Author	Harding, Heather P. Ron, David
Copyright Year	2004
Abstract	Stress-induced eukaryotic translation initiation factor 2 (eIF2) alpha phosphorylation paradoxically increases translation of the metazoan activating transcription factor 4 (ATF4), activating the integrated stress response (ISR), a pro-survival gene expression program. Previous studies implicated the 5' end of the ATF4 mRNA, with its two conserved upstream ORFs (uORFs), in this translational regulation. Here, we report on mutation analysis of the ATF4 mRNA which revealed that scanning ribosomes initiate translation efficiently at both uORFs and ribosomes that had translated uORF1 efficiently reinitiate translation at downstream AUGs. In unstressed cells, low levels of eIF2alpha phosphorylation favor early capacitation of such reinitiating ribosomes directing them to the inhibitory uORF2, which precludes subsequent translation of ATF4 and represses the ISR. In stressed cells high levels of eIF2alpha phosphorylation delays ribosome capacitation and favors reinitiation at ATF4 over the inhibitory uORF2. These features are common to regulated translation of GCN4 in yeast. The metazoan ISR thus resembles the yeast general control response both in its target genes and its mechanistic details.
Starting Page	27
Ending Page	33
Page Count	7
File Format	PDF HTM / HTML
PubMed reference number	15479734v1
Volume Number	167
Journal	The Journal of cell biology
Alternate Webpage(s)	http://ron.cimr.cam.ac.uk/OurPDFs/Lu.JCB.ATF4.2004.pdf
Alternate Webpage(s)	http://ftp.ncbi.nlm.nih.gov/pub/pmc/06/be/200408003.PMC2172506.pdf
Alternate Webpage(s)	http://saturn.med.nyu.edu/research/mp/ronlab/PDF.files/Lu.JCB.ATF4.2004.pdf
Alternate Webpage(s)	http://jcb.rupress.org/content/jcb/167/1/27.full.pdf?with-ds=yes
Language	English
Access Restriction	Open
Subject Keyword	ATF4 gene Activating Transcription Factors Cognitive function: initiation F Factor Frame (physical object) Gene Expression Genetic Translation Process Open Reading Frames Peptide Initiation Factors Reading Frames (Nucleotide Sequence) Ribosomes TCF4 protein, human TRANSCRIPTION FACTOR Translation Initiation Translational Regulation biological adaptation to stress translation reinitiation
Content Type	Text
Resource Type	Article

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